Genetic Variant FBXL18:p.Pro598His (chr7-5491438-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024963.6(FBXL18):c.1793C>A(p.Pro598His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P598R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FBXL18
NM_024963.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.59

Publications

0 publications found

Variant links:

Genes affected

FBXL18 (HGNC:21874): (F-box and leucine rich repeat protein 18) The protein encoded by this gene is a member of a family of proteins that contain an approximately 40-amino acid F-box motif. This motif is important for interaction with SKP1 and for targeting some proteins for degradation. The encoded protein has been shown to control the cellular level of FBXL7, a protein that induces mitotic arrest, by targeting it for polyubiquitylation and proteasomal degradation. Members of the F-box protein family, such as FBXL18, are characterized by an approximately 40-amino acid F-box motif. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains. [provided by RefSeq, Mar 2016]

FBXL18 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024963.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXL18	NM_024963.6	MANE Select	c.1793C>A	p.Pro598His	missense	Exon 4 of 5	NP_079239.3
FBXL18	NM_001321213.2		c.1793C>A	p.Pro598His	missense	Exon 4 of 5	NP_001308142.1	Q96ME1-5
FBXL18	NM_001363441.2		c.1793C>A	p.Pro598His	missense	Exon 4 of 5	NP_001350370.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXL18	ENST00000382368.8	TSL:5 MANE Select	c.1793C>A	p.Pro598His	missense	Exon 4 of 5	ENSP00000371805.3	Q96ME1-4
FBXL18	ENST00000458142.1	TSL:2	c.1442C>A	p.Pro481His	missense	Exon 2 of 3	ENSP00000405896.1	A0A994ENR3
FBXL18	ENST00000948868.1		c.1574C>A	p.Pro525His	missense	Exon 3 of 4	ENSP00000618927.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1432518

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709924

African (AFR)

AF:

0.00

AC:

AN:

33190

American (AMR)

AF:

0.00

AC:

AN:

39506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25484

East Asian (EAS)

AF:

0.00

AC:

AN:

38852

South Asian (SAS)

AF:

0.00

AC:

AN:

82818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5424

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098964

Other (OTH)

AF:

0.00

AC:

AN:

59402

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.1

PhyloP100

9.6

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.50

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.91

MutPred

0.70

Loss of loop (P = 0.0112)

MVP

0.77

MPC

1.6

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.74

Mutation Taster

=18/82

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over